Prediction of the pharmacokinetics of pemetrexed with a low test dose: A proof-of-concept study.

PURPOSE: Pemetrexed is a cytotoxic drug used for the treatment of lung cancer and mesothelioma. The use of a low test dosing of cytotoxic drugs may aid in dose individualization without causing harm. The aim of this proof-of-concept study was to assess if the pharmacokinetics (PKs) of a test dose could predict the PKs of a therapeutic pemetrexed dose. METHODS: Ten patients received both a low test dose (100 µg) and a therapeutic dose of pemetrexed after which plasma concentrations pemetrexed were measured. PK analysis was performed by means of nonlinear mixed-effects modelling. The predictive performances of test dose clearance and renal function towards a therapeutic dose were assessed. RESULTS: The PKs of a pemetrexed test dose were best described by a one-compartment model with linear elimination. A high variability in the administered dose was observed for the test dose, but not for the therapeutic dose. A statistically significant correlation between test dose clearance and therapeutic dose clearance was observed (Spearman's rho: 0.758, P = 0.02). The predictive performance of test dose clearance was worse than renal function: mean predictive error (+95% confidence interval [CI]) 53.9% (50.1-57.6%) vs 19.4% (12.4-26.4%) and normalized root-mean square error (+95% CI) 57.8% (30.5-85.1%) vs 25.7% (20.3-31.0%). CONCLUSION: We show that test dosing of pemetrexed is feasible, but there seems no added value for a low test dosing in the dose individualization of pemetrexed.

Hyperhydration with cisplatin does not influence pemetrexed exposure.

Pemetrexed is a cytotoxic drug for first-line treatment of lung cancer. It is often combined with other anticancer drugs such as cisplatin or carboplatin. In clinical practice, hyperhydration regimens are applied to overcome cisplatin-related nephrotoxicity. As pemetrexed is almost completely eliminated from the body by the kidneys, hyperhydration can result in augmented clearance. Furthermore, administration of large quantities of fluid may increase the volume of distribution of pemetrexed. Pharmacokinetics and, thus, efficacy and toxicity may be influenced by hyperhydration. This has not yet been properly studied. We performed a population pharmacokinetic analysis to assess hyperhydration as a covariate for pemetrexed clearance and for volume of distribution A relevant change was defined as >25% increase in clearance or volume of distribution. In our extensive dataset of 133 individuals, we found that hyperhydration did not significantly or relevantly explain variability in pemetrexed clearance (unchanged, P = .196) or volume of distribution (+7% change, P = .002), despite a power of >99% to detect a relevant change. Therefore, dose adjustments of pemetrexed are not required during hyperhydration with cisplatin.

Highly sensitive quantification of pemetrexed in human plasma using UPLC-MS/MS to support microdosing studies.

Pemetrexed is an antifolate drug approved for the treatment of non-small-cell lung cancer and mesothelioma. Assessing pemetrexed pharmacokinetics after administration of a microdose (100 µg) may facilitate drug-drug interaction and dose individualization studies with cytotoxic drugs, without causing harm to patients. Therefore, a highly sensitive bioanalytical assay is required. A reversed-phase ultra-high performance liquid chromatography method was developed to determine pemetrexed concentrations in human ethylenediaminetetraacetic acid-plasma after microdosing. [13 C5 ]-Pemetrexed was used as the internal standard. The sample preparation involved solid-phase extraction from plasma. Detection was performed using MS/MS in a total run time of 9.5 min. The assay was validated over the concentration range of 0.0250-25.0 µg/L pemetrexed. The average accuracies for the assay in plasma were 96.5 and 96.5%, and the within-day and between-day precision in coefficients of variations was <8.8%. Extraction recovery was 59 ± 1 and 55 ± 5% for pemetrexed and its internal standard. Processed plasma samples were stable for 2 days in a cooled autosampler at 10°C. The assay was successfully applied in a pharmacokinetic curve, which was obtained as a part of an ongoing clinical microdosing study.

Toxicity of pemetrexed during renal impairment explained-Implications for safe treatment.

Pemetrexed is an important component of first line treatment in patients with non-squamous non-small cell lung cancer. However, a limitation is the contraindication in patients with renal impairment due to hematological toxicity. Currently, it is unknown how to safely dose pemetrexed in these patients. The aim of our study was to elucidate the relationship between pemetrexed exposure and toxicity to support the development of a safe dosing regimen in patients with renal impairment. A population pharmacokinetic/pharmacodynamic analysis was performed based on phase II study results in three patients with renal dysfunction, supplemented with data from 106 patients in early clinical studies. Findings were externally validated with data of different pemetrexed dosing regimens. Alternative dosing regimens were evaluated using the developed model. We found that pemetrexed toxicity was driven by the time above a toxicity threshold concentration. The threshold for vitamin-supplemented patients was 0.110 mg/mL (95% CI: 0.092-0.146 mg/mL). It was observed that in patients with renal impairment (estimated glomerular filtration rate [eGFR]: <45 mL/min) the approved dose of 500 mg/m2 would yield a high probability of severe neutropenia in the range of 51.0% to 92.6%. A pemetrexed dose of 20 mg for patients (eGFR: 20 mL/min) is shown to be neutropenic-equivalent to the approved dose in patients with adequate renal function (eGFR: 90 mL/min), but would result in an approximately 13-fold lower area under the concentration-time curve. The pemetrexed exposure-toxicity relationship is explained by a toxicity threshold and substantially different from previously thought. Without prophylaxis for toxicity, it is unlikely that a therapeutic dose can be safely administered to patients with renal impairment.

Simple and Rapid Quantification of the Multi-Enzyme Targeting Antifolate Pemetrexed in Human Plasma.

BACKGROUND: Pemetrexed is an antifolate cytostatic drug that targets multiple enzymes involved in folate biosynthesis and is indicated for treatment of non-small-cell lung cancer and malignant pleural mesothelioma. As evidence for an exposure-response/toxicity relationship is accumulating, dose individualization using therapeutic drug monitoring may be a feasible strategy to optimize treatment. The purpose of this study was to develop a simple, sensitive, high-performance liquid chromatography method with UV detection for quantification of pemetrexed levels in human plasma. METHOD: The method involves a simple protein precipitation, followed by ultra-performance liquid chromatography with ultraviolet detection at a wavelength of 254 nm. Pemetrexed was separated using a mobile phase with a linear gradient and a run time of only 7 minutes. RESULTS: The assay has been validated over the concentration range 0.25-500 mg/L of pemetrexed. Accuracy for this assay ranged from -4.50% to 1.78%, and the within- and between-run coefficients of variation were <3.57%. Pemetrexed in plasma was proven to be stable for 8 months at -40°C. CONCLUSIONS: The bioanalytical method we developed proved to be simple, accurate, precise, and fast. This analytical method is successfully in use for therapeutic drug monitoring and will be used for pharmacokinetic studies.

Effect of conventional hemodialysis on the apixaban plasma concentration.

PURPOSE: Apixaban is a factor Xa inhibitor used in patients undergoing hemodialysis treatment. The objective of this study is to investigate the effect of hemodialysis on apixaban plasma concentrations. METHODS: This observational study is on patients treated with apixaban 2.5 mg twice daily on conventional hemodialysis with standard low-molecular-weight heparin (LMWH) anticoagulation (nadroparin 3800-7600 IU). Plasma blood samples were collected before starting dialysis (t1), 2 h after starting dialysis (t2), and directly after dialysis (t3). Apixaban concentration was measured before and after dialysis. Anti-Xa activity was measured for all three samples. RESULTS: A significant difference was observed between the apixaban concentration before and after dialysis (mean before dialysis 141.03 ng/mL; mean after dialysis 102.71 ng/mL; p = 0.003). Nonetheless, both apixaban plasma concentrations and anti-Xa levels remained within the reference range. Anti-Xa levels had a strong correlation with the apixaban concentrations (r = 0.935, p = 0.000). Thus, anti-Xa activity might be used as a surrogate for apixaban plasma concentration. CONCLUSION: There seems to be no need for dose adjustments of apixaban; co-administration of LMWH next to apixaban might also be unnecessary.

Model-Informed Development of a Cost-Saving Dosing Regimen for Sacituzumab Govitecan.

BACKGROUND: The antibody-drug conjugate sacituzumab govitecan is approved for metastatic triple-negative breast cancer and has shown promising results in various other types of cancer. Its costs may limit patient access to this novel effective treatment modality. OBJECTIVE: The purpose of this study was to develop an evidence-based rational dosing regimen that results in targeted drug exposure within the therapeutic range while minimizing financial toxicity, to improve treatment access. PATIENTS AND METHODS: Exposure equivalent dosing strategies were developed based on pharmacokinetic modeling and simulation by using the published pharmacokinetic model developed by the license holder. The alternative dose was based on the principle of using complete vials to prevent spillage and on the established non-linear relationship between body weight and systemic exposure. Equivalent exposure compared to the approved dosing regimen of 10 mg/kg was aimed for. Equivalent exposure was conservatively defined as calculated geometric mean ratios within the 0.9-1.11 boundaries for area under the concentration-time curve (AUC), trough concentration (Ctrough) and maximum concentration (Cmax) of the alternative dosing regimen compared to the approved dosing regimen. Since different vial sizes are available for the European Union (EU) and United States (US) market, because body weight distributions differ between these populations, we performed our analysis for both scenarios. RESULTS: Dosing regimens of sacituzumab govitecan for the EU (< 50 kg: 400 mg, 50-80 kg: 600 mg, and > 80 kg: 800 mg) and US population (< 40 kg: 360 mg, 40-65 kg: 540 mg, 65-90 kg: 720 mg, and > 90 kg: 900 mg) were developed, based on weight bands. The geometric mean ratios for all pharmacokinetic outcomes were within the predefined equivalence boundaries, while the quantity of drug used was 21.5% and 19.0% lower for the EU and US scenarios, respectively. CONCLUSIONS: With the alternative dosing proposal, an approximately 20% reduction in drug expenses for sacituzumab govitecan can be realized while maintaining an equivalent and more evenly distributed exposure throughout the body weight range, without notable increases in pharmacokinetic variability.

Renal function-based versus standard dosing of pemetrexed: a randomized controlled trial.

PURPOSE: Pemetrexed is a chemotherapeutic drug in the treatment of non-small cell lung cancer and mesothelioma. Optimized dosing of pemetrexed based on renal function instead of body surface area (BSA) is hypothesized to reduce pharmacokinetic variability in systemic exposure and could therefore improve treatment outcomes. The aim of this study is to compare optimized dosing to standard BSA-based dosing. METHODS: A multicenter randomized (1:1) controlled trial was performed to assess superiority of optimized dosing versus BSA-based dosing in patients who were eligible for pemetrexed-based chemotherapy. The individual exposure to pemetrexed in terms of area under the concentration-time curve (AUC) was determined. The fraction of patients attaining to a predefined typical target AUC (164 mg × h/L ± 25%) was calculated. RESULTS: A total of 81 patients were included. Target attainment was not statistically significant different between both arms (89% vs. 84% (p = 0.505)). The AUC of pemetrexed was similar between the optimized dosing arm (n = 37) and the standard of care arm (n = 44) (155 mg × h/L vs 160 mg × h/L (p = 0.436). CONCLUSION: We could not show superiority of optimized dosing of pemetrexed in patients with an adequate renal function does not show added value on the attainment of a pharmacokinetic endpoint, safety, nor QoL compared to standard of care dosing. CLINICAL TRIAL NUMBER: Clinicaltrials.gov identifier: NCT03655821.

A Systematic Evaluation of Cost-Saving Dosing Regimens for Therapeutic Antibodies and Antibody-Drug Conjugates for the Treatment of Lung Cancer.

BACKGROUND: Expensive novel anticancer drugs put a serious strain on healthcare budgets, and the associated drug expenses limit access to life-saving treatments worldwide. OBJECTIVE: We aimed to develop alternative dosing regimens to reduce drug expenses. METHODS: We developed alternative dosing regimens for the following monoclonal antibodies used for the treatment of lung cancer: amivantamab, atezolizumab, bevacizumab, durvalumab, ipilimumab, nivolumab, pembrolizumab, and ramucirumab; and for the antibody-drug conjugate trastuzumab deruxtecan. The alternative dosing regimens were developed by means of modeling and simulation based on the population pharmacokinetic models developed by the license holders. They were based on weight bands and the administration of complete vials to limit drug wastage. The resulting dosing regimens were developed to comply with criteria used by regulatory authorities for in silico dose development. RESULTS: We found that alternative dosing regimens could result in cost savings that range from 11 to 28%, and lead to equivalent pharmacokinetic exposure with no relevant increases in variability in exposure. CONCLUSIONS: Dosing regimens based on weight bands and the use of complete vials to reduce drug wastage result in less expenses while maintaining equivalent exposure. The level of evidence of our proposal is the same as accepted by regulatory authorities for the approval of alternative dosing regimens of other monoclonal antibodies in oncology. The proposed alternative dosing regimens can, therefore, be directly implemented in clinical practice.

The Pharmacoeconomic Benefits of Pemetrexed Dose Individualization in Patients With Lung Cancer.

Neutropenia is a dose-related treatment-limiting and costly adverse event of pemetrexed. We postulate that individualized dosing reduces the incidence of neutropenia. The aims of this study were (i) to investigate the costs of pemetrexed-related neutropenia and (ii) to determine the pharmacoeconomic benefits of individualized dosing of pemetrexed in terms of budget impact, yearly cost savings, and reduction in severe neutropenia. Retrospective data on the treatment of grade 3 or higher neutropenia during pemetrexed-based chemotherapy were collected from three Dutch hospitals to determine the mean healthcare consumption during a neutropenic episode. Subsequently, Monte Carlo simulations were performed using a validated pharmacokinetic/pharmacodynamic model to predict the neutropenia incidence during four cycles for standard dosing of pemetrexed and individualized dosing. The mean costs per neutropenia and the expected neutropenia incidence were combined to calculate the budget impact and cost savings. We found that the average costs per pemetrexed-associated neutropenic episode to be €1,490 (US $1,674). The neutropenia incidence for the standard and individualized pemetrexed dosing strategies were 12.7% and 9.9%, respectively. This resulted in total expected neutropenia-related costs of ~ €3.0 million (US $3.372 million) and €2.4 million (US $2.697 million), respectively. Taking the number of patients eligible for pemetrexed treatment into account, individualized dosing could result in saving €686,000 (US $770,995) on a yearly basis in the Netherlands alone. Individualized dosing of pemetrexed can decrease the incidence of neutropenia and thus result in a significant decrease in neutropenia-related costs and decreased risk of hospitalization or even death while maintaining therapeutic exposure.

Mechanisms, Management and Prevention of Pemetrexed-Related Toxicity.

Pemetrexed is a cytostatic antifolate drug and a cornerstone in the treatment of lung cancer. Although generally well tolerated, a substantial part of the patient population experiences dose-limiting or even treatment-limiting toxicities. These include mucositis, skin problems, fatigue, renal toxicity, and neutropenia. Several studies confirmed that pemetrexed pharmacokinetics can serve as a prognostic factor for the development of toxicity, especially for neutropenia. Preventing and managing toxicity of pemetrexed can help to ensure durable treatment. Several evidence-based strategies are already implemented in clinical care. With the introduction of standard vitamin supplementation and dexamethasone, the incidence of hematological toxicity and skin reactions substantially decreased. In the case of high risk for toxicity, granulocyte colony-stimulating factor can be used to prevent severe hematological toxicity. Moreover, high-dose folinic acid can resolve severe pemetrexed-induced toxicity. There are several experimental options to prevent or manage pemetrexed-related toxicity, such as the use of standard folinic acid, hemodialysis, antidotes such as thymidine, hypoxanthine, and glucarpidase, and the use of therapeutic drug monitoring. These strategies still need clinical evaluation before implementation, but could enable treatment with pemetrexed for patients who are at risk for toxicity, such as in renal impairment.

Rethinking the Application of Pemetrexed for Patients with Renal Impairment: A Pharmacokinetic Analysis.

BACKGROUND: Pemetrexed is used for the treatment for non-small cell lung cancer and mesothelioma. Patients with renal impairment are withheld treatment with this drug as it is unknown what dose is well tolerated in this population. OBJECTIVE: The purpose of our study was to investigate the pharmacokinetics (PK) of pemetrexed in patients with renal impairment. METHODS: A population PK analysis of pemetrexed was performed using non-linear mixed-effects modelling with phase I data obtained from the manufacturer. Additionally, the impact of renal function on pemetrexed PK was assessed with a simulation study using the developed PK model and a previously developed PK model lacking the phase I data. RESULTS: The dataset included 548 paired observations of 47 patients, with a wide range of estimated glomerular filtration rates (eGFR; 14.4-145.6 mL/min). Pemetrexed PK were best described by a three-compartment model with eGFR (calculated using the Chronic Kidney Disease-Epidemiology Collaboration [CKD-EPI] formula) as a linear covariate on renal pemetrexed clearance. Using the developed model, we found that renal clearance accounts for up to 84% (95% confidence interval 69-98%) of total pemetrexed clearance, whereas the manufacturer previously reported a 50% contribution of renal clearance. CONCLUSION: Renal function is more important for the clearance of pemetrexed than previously thought and this should be taken into account in patients with renal impairment. Furthermore, a third compartment may contribute to prolonged exposure to pemetrexed during drug washout.

A limited sampling schedule to estimate individual pharmacokinetics of pemetrexed in patients with varying renal functions.

PURPOSE: Pemetrexed is a widely used cytostatic agent with an established exposure-response relationship. Although dosing is based on body surface area (BSA), large interindividual variability in pemetrexed plasma concentrations is observed. Therapeutic drug monitoring (TDM) can be a feasible strategy to reduce variability in specific cases leading to potentially optimized pemetrexed treatment. The aim of this study was to develop a limited sampling schedule (LSS) for the assessment of pemetrexed pharmacokinetics. METHODS: Based on two real-life datasets, several limited sampling designs were evaluated on predicting clearance, using NONMEM, based on mean prediction error (MPE %) and normalized root mean squared error (NRMSE %). The predefined criteria for an acceptable LSS were: a maximum of four sampling time points within 8 h with an MPE and NRMSE ≤ 20%. RESULTS: For an accurate estimation of clearance, only four samples in a convenient window of 8 h were required for accurate and precise prediction (MPE and NRMSE of 3.6% and 5.7% for dataset 1 and of 15.5% and 16.5% for dataset 2). A single sample at t = 24 h performed also within the criteria with MPE and NRMSE of 5.8% and 8.7% for dataset 1 and of 11.5% and 16.4% for dataset 2. Bias increased when patients had lower creatinine clearance. CONCLUSIONS: We presented two limited sampling designs for estimation of pemetrexed pharmacokinetics. Either one can be used based on preference and feasibility.

Multidimensional profiling of CSF1R screening hits and inhibitors: assessing cellular activity, target residence time, and selectivity in a higher throughput way.

Over the past years, improvements in high-throughput screening (HTS) technology and compound libraries have resulted in a dramatic increase in the amounts of good-quality screening hits, and there is a growing need for follow-on hit profiling assays with medium throughput to further triage hits. Here the authors present such assays for the colony-stimulating factor 1 receptor (CSF1R, Fms), including tests for cellular activity and a homogeneous assay to measure affinity for inactive CSF1R. They also present a high-throughput assay to measure target residence time, which is based on competitive binding kinetics. To better fit k(off) rates, they present a modified mathematical model for competitive kinetics. In all assays, they profiled eight reference inhibitors (imatinib, sorafenib, sunitinib, tandutinib, dasatinib, GW2580, Ki20227, and J&J's pyrido[2,3-d]pyrimidin-5-one). Using the known biochemical selectivities of these inhibitors, which can be quantified using metrics such as the selectivity entropy, the authors have determined which assay readout best predicts hit selectivity. Their profiling shows surprisingly that imatinib has a preference for the active form of CSF1R and that Ki20227 has an unusually slow target dissociation rate. This confirms that follow-on hit profiling is essential to ensure that the best hits are selected for lead optimization.